chrX-50092130-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_001127898.4(CLCN5):c.2362C>T(p.Arg788*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_001127898.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1079529Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 347577
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Dent disease type 1 Pathogenic:1Other:1
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This individual is hemizygous for a known nonsense variant, c.2362C>T, in the CLCN5 gene. This variant creates a premature stop codon (p.Arg788*). c.2362C>T (p.Arg788*) has not been listed in any population databases (i.e. ExAC, ESP or dbSNP). The variant has been reported in five unrelated patients with Dent's disease (Carballo-Trujillo et.al. Nephrol Dial Transplant 2003; 18(4): 717-723, Hoopes et.al. Kidney Int 2004; 65: 1615-1620, Wu et.al. Nephron Physiol 2009; 112: 53-62 & Grand et.al. Kidney Int 2009; 76: 999-1005). Segregation studies were performed by Carballo-Trujillo et.al and c.2362C>T was shown to cosegregate with the disease. In these reports, the variant is described as p.Arg718* (relative to transcript NM_000084.4). Functional studies in Xenopus laevis oocytes showed that this nonsense variant produced a truncated protein product and was lower in abundance in comparison to the wild-type. The truncation affected the cellular localisation of the protein (Grand et.al. Kidney Int 2009; 76: 999-1005). This variant is considered to be pathogenic according to the ACMG guidelines. -
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg718*) in the CLCN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the CLCN5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Dent disease (PMID: 12637640, 31672324). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208000). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLCN5 function (PMID: 19657328). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at